β-Glucocerebrosidase Modulators Promote Dimerization of β-Glucocerebrosidase and Reveal an Allosteric Binding Site
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چکیده
منابع مشابه
Computational Prediction of Structure-Activity Relationships for the Binding of Aminocyclitols to β-Glucocerebrosidase
Glucocerebrosidase (GCase, acid β-Glucosidase) hydrolyzes the sphingolipid glucosylceramide into glucose and ceramide. Mutations in this enzyme lead to a lipid metabolism disorder known as Gaucher disease. The design of competitive inhibitors of GCase is a promising field of research for the design of pharmacological chaperones as new therapeutic agents. Using a series of recently reported mole...
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Glucocerebrosidase (GBA) is a lysosomal β-glucosidase that degrades glucosylceramide. Its deficiency results in Gaucher disease (GD). We examined the effects of active site occupancy of GBA on its structural stability. For this, we made use of cyclophellitol-derived activity-based probes (ABPs) that bind irreversibly to the catalytic nucleophile (E340), and for comparison, we used the potent re...
متن کاملPlant-based oral delivery of β-glucocerebrosidase as an enzyme replacement therapy for Gaucher's disease.
Gaucher's disease (GD), a lysosomal storage disorder caused by mutations in the gene encoding glucocerebrosidase (GCD), is currently treated by enzyme replacement therapy (ERT) using recombinant GCD that is administered intravenously every 2 weeks. However, intravenous administration includes discomfort or pain and might cause local and systemic infections that may lead to low patient complianc...
متن کاملCharacterization of the complex formed by β-glucocerebrosidase and the lysosomal integral membrane protein type-2.
The lysosomal integral membrane protein type-2 (LIMP-2) plays a pivotal role in the delivery of β-glucocerebrosidase (GC) to lysosomes. Mutations in GC result in Gaucher's disease (GD) and are the major genetic risk factor for the development of Parkinson's disease (PD). Variants in the LIMP-2 gene cause action myoclonus-renal failure syndrome and also have been linked to PD. Given the importan...
متن کاملLysosome sorting of β-glucocerebrosidase by LIMP-2 is targeted by the mannose 6-phosphate receptor
The integral membrane protein LIMP-2 has been a paradigm for mannose 6-phosphate receptor (MPR) independent lysosomal targeting, binding to β-glucocerebrosidase (β-GCase) and directing it to the lysosome, before dissociating in the late-endosomal/lysosomal compartments. Here we report structural results illuminating how LIMP-2 binds and releases β-GCase according to changes in pH, via a histidi...
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ژورنال
عنوان ژورنال: Journal of the American Chemical Society
سال: 2018
ISSN: 0002-7863,1520-5126
DOI: 10.1021/jacs.7b13003